Purpose <p>This review aims to provide a comprehensive analysis of stimuli-responsive hydrogels (SRHs) as advanced platforms for biomedical applications. It focuses on comparing natural and synthetic macromolecular systems in terms of their synthesis, responsiveness to physiological and external stimuli, and their utility in achieving controlled drug delivery (DD) and supporting tissue engineering (TE).</p> Method <p>The review synthesizes recent advancements in the field by examining the structural and functional properties of key natural biopolymers, specifically alginate, chitosan, and hyaluronic acid, alongside synthetic smart hydrogel systems. It evaluates their fabrication schemes and the mechanisms governing their stimuli-responsive release kinetics, including responses to temperature, magnetic fields, pressure, and acoustic fields.</p> Results <p>The analysis reveals that both natural and synthetic SRHs exhibit unique characteristics such as high water absorption, biocompatibility, and the ability to undergo reversible phase transitions in response to specific triggers. Natural macromolecules offer inherent biocompatibility and bioactivity, while synthetic systems provide tunable mechanical properties and degradation profiles. Crucially, SRHs demonstrate the capacity for zero-order drug release kinetics, positioning them as prime candidates for next-generation, self-regulated delivery systems. Their adaptive properties are shown to be highly valuable in both controlled drug delivery and tissue engineering contexts.</p> Conclusion <p>Stimuli-responsive hydrogels represent a transformative class of smart biomaterials with significant potential to advance personalized and adaptive therapies. While ongoing challenges related to clinical translation and scalability remain, the versatility and dynamic responsiveness of SRHs open exciting opportunities for the future development of healthcare applications, particularly in integrated DD and TE platforms.</p>